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Rare disease gene association discovery in the 100,000 Genomes Project

by informer
2 minutes read

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Up to 80% of rare disease patients remain undiagnosed even after genomic sequencing, likely due to pathogenic variants in disease–gene associations that have yet to be discovered. To identify such associations, a rare variant gene burden analysis framework for Mendelian diseases was developed and applied to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members in the 100,000 Genomes Project.

This approach uncovered 141 new disease–gene associations, including five recently supported by independent studies. After in silico triaging and expert clinical review, 69 associations were prioritized, with 30 supported by existing experimental evidence. The five strongest associations, based on genetic and experimental data, linked:

  • UNC13A to monogenic diabetes (a known β cell regulator)
  • GPR17 to schizophrenia
  • RBFOX3 to epilepsy
  • ARPC3 to Charcot–Marie–Tooth disease
  • POMK to anterior segment ocular abnormalities

Further validation of these and other associations could lead to new diagnoses, highlighting the clinical impact of large-scale statistical approaches in rare disease–gene discovery.

Read the full article here.

Molecular landscape of congenital vertebral malformations: recent discoveries and future directions

by informer
2 minutes read

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Vertebral malformations (VMs) pose a significant global health problem, causing chronic pain and disability. Vertebral defects occur either as isolated conditions or as part of various congenital disorders, such as Klippel–Feil syndrome, congenital scoliosis, spondylocostal dysostosis, sacral agenesis, and neural tube defects. Although both genetic abnormalities and environmental factors can contribute to abnormal vertebral development, our understanding of the molecular mechanisms underlying many VMs remains limited. Furthermore, there is a lack of resources that consolidate current knowledge in this field.

In this review, a comprehensive analysis of the latest research on the molecular basis of VMs and the association of VM-related causative genes with bone developmental signaling pathways is provided. This study identifies 118 genes linked to VMs, with 98 of them involved in biological pathways crucial for vertebral column formation. Overall, the review summarizes current knowledge on VM genetics and provides new insights into the potential involvement of biological pathways in VM pathogenesis. Additionally, an overview of available data on the role of epigenetic and environmental factors in VMs is provided.

Areas where knowledge is lacking are identified, such as the precise molecular mechanisms through which specific genes contribute to VM development. Finally, future research avenues that could address these knowledge gaps are proposed.

Read the full article here.

International Rare Disease Day

by informer
2 minutes read

Photo credits: National Alliance of People with Rare Diseases

International Rare Disease Day will be celebrated in Plovdiv with colorful raised hands, balloons, and a flashmob. The city has been a part of this global initiative every year since its very beginning.

Founded by EURORDIS and its Council of National Alliances in 2008, the campaign has grown into a worldwide phenomenon. According to World Health Organization statistics, 5% of Bulgaria’s population is affected by rare diseases, which translates to approximately 350,000 people. 75% of these patients are children.

This year, Plovdiv Professional School of Food Technology and Techniques will host the event in collaboration with the National Alliance of People with Rare Diseases and the Municipality of Plovdiv. The school has long demonstrated its social responsibility and commitment to the cause, and has been a key partner for the event for 10 years.

On February 28 (Friday), 2025, starting at 10:30 AM, teachers and students will unite for a flashmob in the school yard to show their support and bring hope to those around the world suffering from rare diseases. Thousands of colorful raised hands will send the powerful message:
“More than you can imagine.”

As tradition goes, colorful balloons will float into the sky, symbolizing the thousands of rare diagnoses that exist globally.

The Socio-Economic Burden of Spinal Muscular Atrophy: A Cost-of-Illness Study in Bulgaria

by informer
3 minutes read

Photo credits: pixabay.com

Elizabet Dzhambazova, Kostadin Kostadinov, Lilia Tsenkova-Toncheva, Fani Galabova, Fares Ezeldin, Georgi Iskrov, and Rumen Stefanov,  from the Medical University of Plovdiv (Faculty of Public Health, Faculty of Medicine), St. George University Hospital and the Institute for Rare Diseases, have conducted a cost-of-illness study on spinal muscular atrophy (SMA) in Bulgaria. Their research assesses the economic burden of SMA from a societal perspective, analyzing healthcare costs, labor productivity losses, and the financial impact on patients and caregivers. This significant study has been published in the prestigious international journal Healthcare (Impact factor: 2.4).

Spinal muscular atrophy is a rare neuromuscular disorder that leads to progressive muscle weakness and disability. The study aimed to evaluate the annual socio-economic burden per SMA patient, incorporating direct healthcare costs, non-healthcare expenses, and indirect costs associated with caregivers’ loss of productivity.

Between 2023 and 2024, nine parents of SMA patients participated in the study, reporting detailed cost data. Among the respondents, seven children had SMA type II, and two had SMA type III. The findings revealed that the median annual socio-economic burden per SMA patient was EUR 254,968.80. The study identified high direct costs, primarily driven by drug expenses, and substantial indirect costs due to caregivers’ lost productivity as the major financial challenges. No utilization of social care and educational services was reported among the participants.

The article emphasizes the urgent need for long-term policy strategies that integrate real-world data collection, performance-based reimbursement models, and holistic support measures for SMA patients and their families. A key recommendation is the development of comprehensive social and financial support programs, as caregiver productivity loss represents a significant portion of the overall economic impact. Read the full article here.

Policy Principles and Recommendations on the Retention and Secondary Use of Residual Dried Blood Spots in Newborn Screening

by informer
2 minutes read

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Newborn screening is a highly successful public health program that saves thousands of lives and is crucial for both the rare disease community and the public.

Residual dried blood spots (DBS), leftover from newborn screening, play a vital role in program operations, public health research, and rare disease studies. However, policy changes must not compromise these lifesaving efforts.

With rising health misinformation and incomplete media coverage about DBS collection, it is essential for the newborn screening system to build trust through clear policies, transparency, and effective communication.

Between April and May 2024, the U.S.-based National Organization for Rare Disorders (NORD®) interviewed 13 patient advocacy organizations representing rare disease groups connected to the Recommended Uniform Screening Panel (RUSP). These interviews led to a working group discussion, involving NORD staff, the Board of Directors’ Advocacy Committee, and newborn screening experts. Together, they developed policy recommendations aimed at strengthening public confidence and ensuring continued participation in newborn screening.

This paper:

  • Explores current challenges and concerns related to residual DBS use.
  • Highlights the rare disease community’s priorities.
  • Establishes guiding principles for evaluating DBS policies.
  • Proposes solutions to address newborn screening program challenges.

Read the full paper here.

Personalized Analytics for Rare Disease Diagnostics

by informer
1 minutes read

Photo credits: pixabay.com

Whole-genome and exome sequencing are standard tools for diagnosing rare and other genetic disorders. However, interpreting the tens of thousands of variants identified in these tests remains a major challenge. This article explores how linking gene expression patterns across multiple tissues to disease phenotypes can aid in identifying disease-causing variants.

To test this hypothesis, classifiers are developed to learn associations between tissue-specific gene expression and disease phenotypes. Using Genotype-Tissue Expression (GTEx) data alongside disease-agnostic variant prioritization methods (CADD or MetaSVM) consistently improves classification accuracy. This approach highlights a previously overlooked way to leverage existing expression data for clinical diagnostics and paves the way for integrating other functional genomic datasets into variant prioritization. Read the full article here.

Scientists and Specialists Discuss Rare Endocrine-Metabolic Diseases

by informer
3 minutes read

Photo credits: MU Plovdiv

“Rare Endocrine-Metabolic Diseases” is the theme of the Sixth Plovdiv Winter Endocrine Days, organized by the Department of Endocrinology and Metabolic Diseases at Medical University – Plovdiv. The event is taking place on the occasion of the 80th anniversary of the university.

The scientific forum will be held on 15 February 2025, from 09:00 to 16:00, in a hybrid format—in-person in the auditorium of Training Building 1 at MU-Plovdiv, and online with free access via the university Zoom platform:
https://zoom.us/j/97862381896

One day earlier, on 14 February 2025 at 11:30, Prof. Maurizio Nordio will deliver an open lecture on the topic “Between the Soul and Science: The Pineal Gland” in Training Building 1 at MU-Plovdiv.

Co-organizers are the Institute for Rare Diseases, MU-Plovdiv, the Center for Rare Diseases at USBALE “Acad. Iv. Penchev“ under the leadership of Prof. Sabina Zakharieva, and the Endocrine Hypertensions Alliance-ALIANS.

Guest lecturers from outside the department’s academic staff are:

  • Prof. Maurizio Nordio (University “La Sapienza,” Rome)
  • Prof. Sabina Zakharieva (USBALE “Acad. Iv. Penchev,” MU-Sofia)
  • Assoc. Prof. Ralitsa Robeva (MU-Sofia)
  • Assoc. Prof. Atanaska Elenkova (Center for Rare Diseases, USBALE “Acad. Iv. Penchev,” MU-Sofia)
  • Prof. Rumen Stefanov (Institute for Rare Diseases, MU-Plovdiv)
  • Prof. Iva Stoeva (Neonatal Screening and Functional Endocrine Diagnostics, SBALDB “Prof. Ivan Mitev,” MU-Sofia)
  • Assoc. Prof. Katya Todorova (Head of the Endocrinology Clinic, UMBAL “Dr. G. Stranski,” MU-Pleven)

Photo credits: MU Plovdiv

We invite you to join us in discussing the latest trends and advances in the field of rare endocrine-metabolic diseases!

Source: Medical University of Plovdiv

Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses

by informer
2 minutes read

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Accurate identification and interpretation of genomic variants are essential for diagnosing rare diseases. The Solve-Rare Diseases Consortium (Solve-RD), a collaboration of clinical and molecular scientists from 37 expert centers across Europe, compiled a resource of clinical, pedigree, and genomic data (94.5% exomes, 5.5% genomes) from 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases, across 6,004 families.

Through a collaborative, two-level expert review infrastructure, genetic diagnoses were made in 506 families (8.4%). Of the 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions, many located in novel disease genes, recently reclassified variants in ClinVar, or those reclassified by expert consensus within Solve-RD. Bioinformatics analyses helped identify the remaining 15.9% of variants (88). Additionally, ad hoc expert reviews diagnosed 249 families (4.1%), resulting in an overall diagnostic yield of 12.6%.

The infrastructure and collaborative networks established by Solve-RD provide a valuable blueprint for future large-scale international efforts. This resource is now open to the global rare-disease community for phenotype, variant, and gene queries, as well as genome-wide discoveries. Read the full article here. Read the full article here.

ERN GENTURIS Guidelines on Diagnosis, Genetic Counselling, and Management of Constitutional Mismatch Repair Deficiency

by informer
3 minutes read

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Constitutional mismatch repair deficiency (CMMRD) is a rare genetic disorder caused by mutations in both copies of mismatch repair (MMR) genes. First identified 25 years ago, it is associated with an extremely high lifelong risk of cancer, including haematologic, brain, and gastrointestinal malignancies, as well as non-cancerous features. The understanding of this condition has advanced, and new diagnostic assays for CMMRD have been developed. Surveillance protocols should be updated based on recent observational studies evaluating their effectiveness.

A team of 72 experts from the European Reference Network GENTURIS and the European care for CMMRD consortium, along with a patient representative, developed recommendations for CMMRD diagnosis, genetic counselling, surveillance, quality of life, and clinical management. These were based on a systematic literature search, comprehensive review, and a modified Delphi process. Recommendations for the diagnosis of CMMRD provide testing criteria, propose strategies for CMMRD testing, and define CMMRD diagnostic criteria. Recommendations for surveillance cover each CMMRD-associated tumour type and contain information on starting age, frequency, and surveillance modality. Recommendations for clinical management cover cancer treatment, management of benign tumours or non-neoplastic features, and chemoprevention. Recommendations also address genetic counselling and quality of life.

Based on existing guidelines and currently available data, 82 recommendations to enhance and standardize care for patients with CMMRD in Europe are presented in this article. These recommendations are intended as guidelines and can be adjusted based on individual decisions. Read the full article here.

Rare primary liver cancers: An EASL (European Association for the Study of the Liver) position paper

by informer
1 minutes read

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In recent years, owing to advances in our understanding of hepatocarcinogenesis, rare primary liver cancers (PLCs), including combined hepatocellular-cholangiocarcinoma, fibrolamellar carcinoma, and hepatic epithelioid hemangioendothelioma have garnered increased attention.

In this position paper, an international panel of experts representing oncology, hepatology, pathology, radiology, surgery, and molecular biology has summarised the available information and evidence on the pathogenesis, diagnosis, and treatment of rare PLCs.

While clinical trials of systemic treatments are underway for some rare PLCs, it is evident that more research, involving national and international collaboration, is required. Read the full document here.

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